Preparation of 9 11-dichloro steroids

ABSTRACT

A PROCESS FOR PREPARING 9,11-DICHLORO STEROIDS WHICH INVOLVES THE STEP OF TREATING A 9A-UNSUBSTITUTED-11B-HYDROXY STEROID WITH THIONYL CHLORIDE AND CHLORINE OPTIONALLY IN INERT LIQUID REACTION MEDIA CONTAINING A TERTIARY AMINE. THE 9,11-DICHLORO STEROID PRODUCTS ARE KNOWN, USEFUL ANTI-INFLAMMATORY AGENTS.

United States Patent Oflice 3,642,780 PREPARATION OF 9,11-DICHLOR STEROIDS Francisco Alvarez, Sunnyvale, Calif., assignor to Syntex Corporation, Panama, Republic of Panama No Drawing. Filed Dec. 19, 1969, Ser. No. 886,768 Int. Cl. C07c 169/00 U.S. Cl. 260-23955 16 Claims ABSTRACT OF THE DISCLOSURE A process for preparing 9,11-dichloro steroids which involves the step of treating a 9a-unsubstituted-ll/i-hydroxy steroid with thionyl chloride and chlorine optionally in inert liquid reaction media containing a tertiary amine. The 9,11-dichloro steroid products are known, useful anti-inflammatory agents.

The present invention relates to advances in organic process chemistry. More particularly, the present invention is directed to a new one step method useful for preparing 9,1l-dichloro steroids which are known, useful anti-inflammatory agents.

Heretofore, 9,11-dichloro steroids have been prepared by procedures requiring several steps. One involves esterifying an 1lfl-hydroxy compound, eliminating the ester to form the corresponding A compound, and finally di halogenating the A double bond. Another even more involved procedure proceeds from the 9,1l-oXido compound, thence to the 9a-chloro-1lfi-hydroxy compound, thence the 9a-chloro-1l-keto compound, thence to the 90cchloro-l IOt-hYdI'OXY compound, thence to a 9et-chloro-11aester, and thence to the 90,llfi-di0hl0t0 compound, the latter chlorination-replacement occurring with configurational inversion. These and other involved methods possess the disadvantages of several steps, several seemingly circuitous.

Now it has been discovered that 90:,lll3-dlChl0fO steroids can be prepared in a single step from 9u-unsubstituted-llB-hydroxy starting compounds. The process of the present invention consists essentially of the step of reacting a 9a-unsubstituted-llfl-hydroxy steroid with a reagent comprising thionyl chloride and chlorine to prepare the corresponding 9a,1l,8-dichloro steroid. In accordance with this invention, therefore, 9a,l1[3-dichloro compounds are prepared from 9a-unsubstituted-1l5-hydroxy compounds in a single step. This process can be depicted by the following equation of steroid partial formulas:

In the practice of the process of the present invention, a 9ot-unsubstituted-1lfi-hydroxy steroid is reacted together with thionyl chloride and chlorine. The reaction preferably is conducted in inert liquid reaction media. The reaction is further preferably conducted in the presence of tertiary amine. The reaction is further conducted at temperatures ranging from about -10 C. or less to about C. or more and for a period of time ranging from about 1 minute to about 30 minutes or more. Higher or lower temperatures and/or longer reaction times can be employed depending upon choice of substrate, liquid reaction media (if any), tertiary amine (if any), and other, physical characteristics which may be employed such as stirring, use of pressure whether super 3,642,780 Patented Feb. 15, 1972 or sub atmospheric. In general, these equivalent modifications are within the usual and ordinary skill in the art and, as such, are included within the scope hereof.

Suitable inert, liquid reaction media, if employed, are provided by halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; ethers such as tetrahydrofuran, diethyl ether, and dioxane; sulfoxides such as dimethylsulfoxide, diethylsulfoxide, and tetramethylenesulfoxide; carboxylic acids such as acetic acid, trifluoroacetic acid and trimethylacetic acid; or suitable mixtures of one or more of the foregoing.

Suitable tertiary amines, if employed, are provided by pyridine, dimethylaniline, lutidine, collidine, trimethylamine, triethylamine, and the like, or suitable mixtures of one or more of the foregoing.

In the preferred embodiments hereof, the reaction is practiced with the benefit of each of an inert, liquid reaction media and a tertiary amine. In these embodiments, halogenated hydrocarbons and pyridine are respectively preferred.

The reaction consumes the reactants upon the basis of one mole of 9a-unsubstituted-1lfi-hydroxy starting steroid per mole each of thionyl chloride and chlorine. However, the amounts of the reactants to be employed are not critical, some of the desired 9u,l1B-dichloro steroid product being obtained when employing any proportions thereof. In the preferred embodiments, the reaction is conducted by reacting from about 0.9 to about 5.0 moles or more each of thionyl chloride and chlorine per mole of starting steroid; the tertiary amine is employed in amounts ranging from about 1 to or more moles per mole of starting steroid; and the inert liquid reaction media in solvent amounts.

In the practice of the process step, the reactants are contacted and maintained together in any convenient order or fashion and within the given temperature range for a period of time sufficient to produce product. Following reaction, the product can be separated and isolated via any conventional technique such as decantation, filtration, extraction, evaporation, distillation, and chromatography.

In one preferred embodiment, the thionyl chloride and chlorine are dispersed in inert liquid reaction media and the resultant mixture then added to a mixture of starting steroid dispersed in the same or different inert liquid reaction media and tertiary amine.

The present invention is useful for the preparation of 9a,1lfi-dichloro steroids generally. The 9a,l1,8-dichloro steroid products hereof are known compounds useful as anti-inflammatory agents. In a particularly preferred embodiment, the present invention is useful for the preparation of 9a,llfi-dichloro steroids of the following Formula A:

wherein R is hydroxy or the conventional hydrolyzable esters thereof, bromo, chloro, or fiuoro;

R is hydroxy or the conventional hydrolyzable esters thereof;

R is u-methyl, ,B-methyl, methylene, hydroxy or the conventional hydrolyzable esters thereof, or, when taken together with R the group in which each of R and R is hydrogen, lower alkyl, monocyclic cycloalkyl, or monocyclic aryl;

R is hydrogen, methyl, chloro, or fluoro; and each of Z and Z is a carbon-carbon single bond or a carboncarbon double bond.

The compounds of the present invention particularly as depicted by Formula A are anti-inflammatory agents useful in the treatment of contact dermatitis, arthritis, and so forth. As such, they can be used, in accordance with the ordinary skills of the art, in the same manner as other known anti-inflammatory agents, such as fluocinolone acetonide.

The starting 9u-unsubstituted 11B hydroxy steroids preferably contain the desired elaborative groups at the other sites of the molecule. However, these optional elaborative groups may be introduced, if desired, after the principal process hereof. Thus, the process of the present invention can be practiced upon elaborated starting compounds or starting compounds capable of further elaboration after the principal reaction, particularly in accordance with the scope of the compounds depicted by Formula A above. In the preferred embodiments, A unsaturation is introduced after the principal reaction hereof such as with chloranil. Similarly, hydroxy groups other than the llfi-hydroxyl are suitably protected during the principal reaction hereof such as by forming a conventional ester thereof. When employing a 9a-unsubstituted- 1119,21-dihydroxy starting compound, for example, the 9oz,11,B,21-tIiChl0l'0 product is prepared.

The starting 9a-unsubstituted 11,3 hydroxy starting compounds are known and can be prepared via methods known per se.

The term conventional hydrolyzable esters," as used herein, refers to those hydrolyzable carboxylic ester groups conventionally employed in the synthetic hormone art such as those derived from hydrocarbon carboxylic acids. These hydrolyzable carboxylic esters are derived from both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from 1 to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-B,;8-dimethylglutarate, acetoxyacetate, 2-chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, fi-chloropropionate, trichloroacetate, fl-chlorobutyrate, and the like.

The term lower alkyl as used herein, denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, the various isomers thereof. The term monocyclic cycloalkyl denotes cyclopentyl and cyclohexyl. The term monocyclic aryl denotes phenyl and substituted phenyl such as p-methylphenyl.

The following examples are provided to illustrate the present invention. As such, however, they should be construed merely as illustrative and not as limitative upon the overall scope hereof.

EXAMPLE 1 Thionyl chloride (3.6 grams) is dispersed in 250 milliliters of carbon tetrachloride at room temperature. Chlorine gas is bubbled through the resultant mixture at room temperature until the molar amount of chlorine dispersed in the mixture approximates the molar amount of thionyl chloride present. A steroidal solution is prepared at room temperature by dispersing 6a-fluoro-16a, 17a-isopropylidenedioxy-2l-acetoxy-pregna 1,4 dienllB-ol-3,20-dione (23.8 grams) in ml. of methylene chloride containing 4 milliliters of pyridine. The thionyl chloride, chlorine, carbon tetrachloride mixture is then added to the steroidal solution at room temperature in a portion-wise fashion with stirring. After the addition, the resultant reaction mixture is allowed to stand at room temperature for five minutes. After this time, the reaction mixture is washed with dilute hydrochloric acid and then water to a neutral pH. The washed mixture is then dried over sodium sulfate and the dried mixture evaporated to provide the 6a-fluoro-9a,llfi-dichloro-l6a, l7a-isopropyl-idenedioxy-Zl-acetoxypregna 1,4 diene- 3,20-dione product which mu be further purified by recrystallization from methylene chloride/hexane.

EXAMPLE 2 One molar equivalent each of thionyl chloride and chlorine are dispersed in 1 liter of chloroform at room temperature. Ten millimoles of 60: fluoro-16u,17a-isopropylidenedioxypregna 1,4 theme-116,21 diol-3,20- dione is dispersed in 100 ml. of chloroform containing 10 ml. of triethyl amine at room temperature. To the resultant steroidal mixture are added 10 ml. of the thionyl chloride, chlorine, chloroform mixture at room temperature at a portionwise fashion with stirring. The resultant reaction mixture is cooled to and maintained at 0 C. for one hour while stirring. After this period of time, it is washed with dilute hydrochloric acid and then repeatedly with water to neutrality. The washed mixture is dried over sodium sulfate and evaporated to provide the 6mfluoro-9a,1 1 8,21-trichloro-16a, 17a isopropylidenedioxypregna-l,4-diene-3,20-dione product which can be further purified by recrystallization from acetone/hexane.

EXAMPLE 3 The procedure of Example 2 is repeated, with similar results, employing methylene chloride and lutidine in the preparation of the steroidal mixture in lieu of chloroform and triethyl amine. In addition, the reaction is conducted at 30 C. for a period of five minutes.

EXAMPLE 4 The procedure of Example 2 is repeated in the absence of tertiary amine, with similar results.

EXAMPLE 5 The procedure of Example 2 is repeated in the absence of chloroform, with similar results.

EXAMPLE 6 The procedure of Example 4 is repeated in the absence of chloroform, with similar results.

EXAMPLE 7 The procedure of Example 2 is repeated using, in addition to chloroform, one of dioxane, tetrahydrofuran, and acetic acid, with similar results in each instance.

EXAMPLES 8-30 In accordance with the foregoing methods the starting compounds listed in column B below are treated with thionyl chloride and chlorine to respectively provide the products listed in column C below.

Column B dlone. ltla-methyl-17a-acetoxypregna-l,4-

diene-llB,2l-diol-3,20-dione.

lfia-methyl-17a,21-dlacetoxypregna-1,4-(1lene-llB-ol-3,20- dione 6a-fluoro-l6a-methyl-17,21-diacetoxypregna-lA-diene-l113-01-3, 20-dio11e.

6a-methyl-17a-aeetoxypregna-1,

4-diene-11fl,21-diol-3,20-dione.

6a-methyl-17a,21-diacetoxypregna-l,4-diene-11B-ol-3,20-d10ne.

16a,17a,21-triacetoxypregna-l,4-

diene-11fl-ol-3,20-dione.

17a-acetoxypregna-1,4-dieue-1lfi,

21- -3 21-dione.

17a,21-diacetoxypregna-1,4-diene- 11Bo13,20dione.

1(SB-methyI-Ua-acetoirypregna-1, 4-dlene-l1fl,21-diol-3,20-dione.

17g-acetoxypregnA-enel113,21-(1101- ue. 17a,21-diacetoxypregn-4-en-115-01-3,

20-dione. 6a,21-difluoro-16a,17a-isopropy1idenedioxypregn+en-l1fiol-3, 20-dione. fia-chloro-lfia,17a-isopropyl1- denedioxy-Zl-acetoxypregnapregua-1,4,6-trieu-1lfl-ol-3,20- dione. 6a,21-diehloro-16a,17a-isopropylidenedioxypregna-1,4,6-trieue- 11fi-ol-3,20-dione. fia-fluoro-16a-methyl-17a-acetox3 2l-trimethylacetoxypregna-l, 4-diene-11B-ol-3,20-dione.

Column 9a,1119,21-trichloro-16u,17a-

isopropylidenedioxypregna-l,4- diene-3,20-dione. 6a-fluoro-9a,115,21-trichloro- 16a,17a-isopropylidenedioxypregna-l,4 diene-3,20-dione. 611,901,11B,21-tetrachloro-16a,17a-

isopropylidened1oxypregna-l,4- diene-3,20-dione. 6rx,9a,11B-trlchl0tO-16a,17a-iSO- propylideneliloxy-21-fluoropregna-l,4'diene-3,20-dione. 6a,21-diflll0l0 -9a,11fl-di0hl0l0 16a,17a-isopropy1idenedioxypregna-l,4-diene3,20-dione. 901,1lfl-dichloro16a,17a-isopropylidenedioxy-Zl-fiuoropregna- 1,4-dlene-3,20dione. 9a,11B,21-trleh1oro-16u-methyl- 17a-acetoxypregna-1,4-diene- 3,20-dione. 9a,1lfi-diehloro-lGa-methyl-Ua,

21-diacetoxypregna-1,4-diene-3, 20-dione. fia-fluoro-Qa,115,21-trichloro-l6amethyI-Ha-acetoxypregnal,4-diene-3,20-dione. 6oz-fl11010-9a,11B-dlCl1l0IO-16amethyl-17a ZI-diacetoxypregna- 1,4-dieno-3, O-dione. 6a-methyl-9a,11,8,21-trichloro- 1 7a-ace toxypregna-1,4-diene-3, YD-dione. 6a-m0thy1-9a,11B-d10h101O-170:,21-

diaeetoxypregna-lAdieu-3,

21- one. 911,1lfl-diohlorol6a,17a,21-triaoetoxypregna-1,4-diene-3, Qfi-dione. 9a,11B,21-triehloro-17a-acetoxypregna-l,4-diene 3,20-dione. 9a,11B-dichloro-17a,21-diaceltioxypregna-l,4diene-3,20-

one. 9a,1113,21-triohloro-16fl-methyl-17aaeotoxypregna-l,4-diene-3, 20-dione. 9a,11B-dicl11oro-16fl-methyl-17a,

21-diacetoxypregna-1,4-diene-3, 20-dione. 9a,115,ZI-trichloro-17aaeetoxypregn-4ene-3,20-dione. 901,11fl-dichloro-l7a,21-diacetoxypregn-4-ene-3,20dione. 6u,21'difl11010-9a,11fl-di0h10r0'16a, l7a-isopropylidenedioxypregu- 4-en3,20-dione. 611,9a,11B-tricl1l0r0-16a,17aisopropylidenedioxy-21- acetoxypregna-l,4,6-trien-3, 20-dione. 601,904,11fl,21-tetraehloro-16a,17aisopropylidenedioxypregna l, 4,6-triene-3,20-dione. fia-fluorO-Qa,11B-diGhloY0-l6amethyl-l7a-acetoxy-2l-trimethylacetoxypregna-1,4- diene-3,20-dione.

The following procedures illustrate the manner by which C-16 and/or C-2l ester can be hydrolyzed so as to prepare the free hydroxy compounds and the manner by which A unsaturation can be introduced, each after the principal reaction hereof:

A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5 ml. of methanol is added over 30 minutes to a refluxing solution of l g. of 6a-fluoro-9oi, 11B-dichloro-16a,l7a-isopropylidenedioxy 21 acetoxypregna-l,4-diene-3,20-dione in 30 ml. of methanol under nitrogen. The solution is refluxed for 2 hours, cooled, neutralized with acetic acid and concentrated under reduced pressure. After the addition of water, the solid which forms is collected by filtration and dried to yield 6a-fluoro-9a,11,B dichloro 1611,1711 isopropylidenedioxypregna-1,4-dien-21-ol-3,20-dione which is recrystallized from acetone:hexane.

A mixture of 1 g. of 6oc-fiL10r0-9ot,llfi-dlClllOIO-lGu, 17a isopropylidenedioxypregna 1,4 dien-2l-ol-3,20- dione, 2 g. of chloranil, 15 ml. of ethyl acetate and ml. of acetic acid is refluxed under nitrogen for 96 hours. The mixture is then cooled and washed with cold aqueous sodium hydroxide until the washings were colorless. The organic solution is dried over sodium sulfate and the ethyl acetate removed by evaporation. Upon chromatography of the residue on neutral alumina there is obtained 6a-fluoro-9a,1lB-dichloro-16a,17a-isopropylideuedioxypregna l,4,6-triene-3,20-dione which may be further purified by recrystallization from acetone: hexane.

In accordance with the foregoing methods, the following compounds are prepared:

6,8-methyl-6a,7u-difluoromethylene-9u, 1 1 B-dichloro- 16 a, 17u-isopropylidenedioxypregna- 1, 4-dieue-21-ol- 3 ,20-dione, 65,911, 1 1 fl-Il'lChIOI'O-G0:,7a-diflUOIOII16thYl6I16- l 6u-methylpregnal,4-diene-17a,21-diol-3 ,20-dione, 6 3,21-difluoro-6a,7a-difluoromethylene-9a,1 l ft-dichloro- 16oz, l7wisopropylidenedioxypregna-1,4-diene- 3 ,20-dione, 6a,7a-methylene-9a,11fl-dichloro-21-fluoropregn-4-ene- 17a-ol-3,20-dione, 6,6-difluoro-9a', 1 IB-dichloro-l 6a-methylpregna-1,4-

diene-17a,21-diol3,20-dione, 6,6-difll10l0-9a,1 lfl-dichloro-l6a,17u-isopropylidenedioxypregna-1,4-diene-21-ol-3 ,20-dione, 6,6-difluoro-9 oc,l 1fi-dichloro-16a,17ot-cyclohexylidenedioxypregna- 1 ,4-diene-2 1-01-3 ,20-dione, 6,6-difluoro-9oal Iii-dichloro-16a,17u-benzylidenedioxypregna-1,4-diene-2l-ol-3 ,20-dione, and 6,6-difluoro-9a,l lB-dichloro-16a, 17a-methylphenylmethylenedioxypregna-l ,4-diene-21-ol-3 ,20-dione.

What is claimed is:

1. The process useful for preparing a 9u,ll 3-dlChl0IO steroid which consists essentially of the step of reacting the corresponding Q'a-IJIISUbStitUtEd-IlB-hYdlOXY steroid with a reagent comprising thionyl chloride and chlorine.

2. The process according to claim 1 conducted in inert liquid reaction media.

3. The process according to claim 2 conducted in the presence of tertiary amine.

4. The process according to claim 3 conducted at from about 10 C. to about 30 C.

5. The process according to claim 3 wherein there is prepared a compound selected from those represented by by the following formula:

wherein R is hydroxy or the conventional hydrolyzable esters thereof, bromo, chloro or fiuoro;

R is hydroxy or the conventional hydrolyzable esters thereof;

R is u-methyl, ,B-methyl, methylene, hydroxy or the conventional hydrolyzable esters thereof, or, when taken together with R the group in which each of R and R are hydrogen, lower alkyl, monocyclic cycloalkyl or monocyclic aryl;

R is hydrogen, methyl, chloro or fluoro; and each of Z and Z is a carbon-carbon single bond or a carboncarbon double bond.

6. The process according to claim 3 wherein out-fluoro- 9a,11 3 dichloro 16a,17u isopropylidenedioxypregna- 1,4-dien-21-ol-3,20-dione is prepared.

7. The process according to claim 3 wherein 601,21- difll10lO9oc,l 1B dichloro 1605,1741 isopropylidenedioxypregna-1,4-diene-3,20-dione is prepared.

8. The process according to claim 3 wherein 6oc-fil1010- 90:,1 1 3,21 trichloro 16a,17a-isopropylidenedioxypregna- 1,4-diene-3,20-dione is prepared.

9. The process useful for preparing a 9a,11fl-dichloro steroid which consists essentially of the step of reacting the corresponding 9a-unsubstituted-llfi-hydroxy steroid with thionyl chloride and chlorine in inert liquid reaction media and tertiary amine.

10. The process according to claim 9 wherein the inert liquid reaction media is a chlorinated hydrocarbon.

11. The process according to claim 9 wherein said reagent comprises thionyl chloride and chlorine in substantially equal molar amounts.

12. The process according to claim 10 wherein the tertiary amine is pyridine.

13. The process according to claim 12 conducted at from about 10 C. to about 30 C.

14. The process according to claim 13 wherein 6afluoro 901,11 3 dichloro 16a,17a isopropylidenedioxypregna-1,4-dien-21-0l-3,20-dione is prepared.

15. The process according to claim 13 wherein 611,21- difiuoro 9a,1 1 S dichloro 16a,l7u-isopropylidenedioxypregna-l,4-diene-3,20-dione is prepared.

'16. The process according to claim 13 wherein 6afluoro 9a,11}3,21 trichloro-16a,17a-isopropy1idenedioxypregna-l,4-diene-3,20-dione is prepared.

No references cited.

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R. 260-39745 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 642, 780 Dated February 15, 1972 Invent Francisco Alvarez It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, lines 55 to 56, "SO CI Cl should be 9 Signed and sealed this 5th day of September 1972.

(SEAL) Attest:

EDWARD M..FLETCHER,JR. Attesting Officer ROBERT GOTTSCHALK Commissioner of Patents FORM PO-105O (10-69) USCOMM. 0 75. :59

@- u.s. GOVERNMENT PRINTING OFFICE: 1969 0-366-334 

